CN102812020B - Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same - Google Patents
Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same Download PDFInfo
- Publication number
- CN102812020B CN102812020B CN201180005610.5A CN201180005610A CN102812020B CN 102812020 B CN102812020 B CN 102812020B CN 201180005610 A CN201180005610 A CN 201180005610A CN 102812020 B CN102812020 B CN 102812020B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- acid
- described formula
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 Cc1ccc(*NN=C[C@](C2)C([N+]([O-])=O)=CC(OC)=C2OC)cc1 Chemical compound Cc1ccc(*NN=C[C@](C2)C([N+]([O-])=O)=CC(OC)=C2OC)cc1 0.000 description 2
- FJRIRZXCUWRAGP-UHFFFAOYSA-N O=C(C(Oc1c2cccc1)=CC2=O)Sc1nc2ccccc2[s]1 Chemical compound O=C(C(Oc1c2cccc1)=CC2=O)Sc1nc2ccccc2[s]1 FJRIRZXCUWRAGP-UHFFFAOYSA-N 0.000 description 2
- GYPCSTPEXLHCEY-UHFFFAOYSA-N COc(cc(C(N=N)=N)c([N+]([O-])=O)c1)c1OC Chemical compound COc(cc(C(N=N)=N)c([N+]([O-])=O)c1)c1OC GYPCSTPEXLHCEY-UHFFFAOYSA-N 0.000 description 1
- DGOOLMGPMIHRFY-UHFFFAOYSA-N COc1cc(CCN(CCc(cc2)ccc2N)C2)c2cc1OC Chemical compound COc1cc(CCN(CCc(cc2)ccc2N)C2)c2cc1OC DGOOLMGPMIHRFY-UHFFFAOYSA-N 0.000 description 1
- DGOOLMGPMIHRFY-UHFFFAOYSA-O COc1cc(CCN(CCc(cc2)ccc2[NH3+])C2)c2cc1OC Chemical compound COc1cc(CCN(CCc(cc2)ccc2[NH3+])C2)c2cc1OC DGOOLMGPMIHRFY-UHFFFAOYSA-O 0.000 description 1
- UTBVIMLZIRIFFR-UHFFFAOYSA-N CSc1nc(cccc2)c2[s]1 Chemical compound CSc1nc(cccc2)c2[s]1 UTBVIMLZIRIFFR-UHFFFAOYSA-N 0.000 description 1
- RVMGXWBCQGAWBR-UHFFFAOYSA-N OC(C(Oc1ccccc11)=CC1=O)=O Chemical compound OC(C(Oc1ccccc11)=CC1=O)=O RVMGXWBCQGAWBR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
According to the present invention, a method for preparing tetrazole methanesulfonic acid salts comprises an acylation reaction using a novel 4-iodine-4H-chromene-2-carbothionic acid S-benzothiazole-2-yl ester. The method of the present invention can shorten a reaction time and improve safety as compared to conventional methods, and can prepare high-purity tetrazole methanesulfonic acid salts at a high yield rate without using a column chromatography method.
Description
Technical field
The present invention relates to the new compound of method for the preparation of tetrazolium mesylate and use thereof.
Background technology
4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl }-2H-tetrazolium-5-base)-4,5-Dimethoxyphenyl] pharmacy acceptable salt of-amine, as P-glycoprotein inhibitors, as multidrug resistance inhibitor.WO2005/033097 PCT openly discloses its preparation method.
According to the disclosure, as shown in reaction scheme 1 and 2, based on the compound (1 and 3) of nitro in solvent (such as methyl alcohol, ethanol, chloroform, methylene dichloride, tetrahydrofuran (THF), ether and hexane toluene), under the existence of metal catalyst (such as palladium, platinum and zinc), experience hydrogenation to obtain aminocompound (2 and 4).Then condensation reagent (such as 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is used, N, N-bicyclic ethyl carbodiimide, N, N-DIC and 1-cyclohexyl-3-(2-morpholinyl ethyl) carbodiimide methyl tosylate), under the existence of catalyzer (such as 4-(dimethylamino) pyridine), at solvent (such as methylene dichloride, chloroform, N, dinethylformamide, tetrahydrofuran (THF) and 1, 4-dioxane) in make the compound of gained through acidylate, to obtain the tetrazole compound (5) as end product.
reaction scheme 1
reaction scheme 2
But due to the application in scale operation of hydrogen and metal catalyst, traditional method may cause potential safety hazard (such as blast and fire).Simultaneously, in order to be separated pure tetrazole compound, traditional method needs the purge process using further silica gel column chromatography, and owing to being limited to column dimensions in column chromatography and applied sample amount, therefore described silica gel column chromatography can not be actually used in scale operation.In addition, due to for the high price chromatographic column packing material of chromatography process, silica gel and a large amount of eluents, described process need high operation cost.
Summary of the invention
Therefore, the object of the present invention is to provide the novel method for the preparation of tetrazolium mesylate.
Another object of the present invention is to provide the new compound that can be used in preparing tetrazolium mesylate, and for the preparation of the method for described compound.
According to an aspect of the present invention, which provide the method for the tetrazolium mesylate for the preparation of formula (I), described method comprises the following step:
The compound of the compound acylation formula (III) of employing formula (II), to obtain the compound of formula (IV); With
Methylsulfonic acid is joined in the compound of formula (IV).
According to another aspect of the present invention, which provide the compound of formula (II), it can be used in preparing tetrazolium mesylate.
According to another aspect of the present invention, which provide the method for the compound of preparation formula (II), under described method is included in the existence of triphenylphosphine and alkali, adopt the step of the compound of formula (VI) and the compound reaction of formula (V).
Embodiment
Hereinafter, will describe the present invention.
Preparation in accordance with the present invention application acylation process; described acylation process use new compound (4-oxo-4H-chromene-2-carbothionic acid S-benzothiazole-2-base ester) replaces the condensation reagent in traditional method; obtain that there is highly purified tetrazolium mesylate with high yield, without the need to extra purge process (such as column chromatography).
As shown in following reaction scheme 3, method for the preparation of tetrazolium mesylate according to the present invention comprises: (step 1) adopts the compound of the compound acylation formula (III) of formula (II), to obtain the compound of formula (IV); Methylsulfonic acid joins in the compound of the formula (IV) obtained in above-mentioned steps by (step 2).
reaction scheme 3
Wherein Me represents methyl group.
First, the compound of formula (II) and formula (III) experiences acidylate to obtain the compound of formula (IV) in polar aprotic solvent.
Particularly; the ester cpds of formula (II) and compound acidylate in polar aprotic solvent of formula (III); described polar aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), ethyl ester, acetone, N; dinethylformamide, acetonitrile, methyl-sulphoxide and composition thereof, preferred methylene dichloride.After acidylate completes, add methyl alcohol wherein so that make its inactivation of the formula (II) remained.Then, acetone is added wherein for purifying the compound with 98% or more highly purified formula (IV) naturally and effectively can be produced.
In acidylate, preferably with the compound of the amount applying equation (II) of 1 to 5 equivalent of the compound of the formula (III) based on 1 equivalent.
In order to make its inactivation of the formula (II) remained after acidylate, preferably with 1 to 2 volume and weight ratio (v/w) apply methyl alcohol, that is, the formula (II) based on 1g compound within the volume range of 1 to 2mL.
Equally, acetone may be used for the purifying in acidylate, and wherein the preferred form of acetone is the aqueous solution, and more preferably 95% aqueous acetone solution.Preferably the formula (III) based on 1g compound within the volume range of 35 to 45mL, apply acetone.
For next step, methylsulfonic acid is joined in the compound of the formula (IV) obtained in step before, with the tetrazolium mesylate of production (I).
Particularly, the tetrazole compound of the formula (IV) obtained in step is before dissolved in organic solvent (such as chloroform and methyl alcohol), then adds methylsulfonic acid wherein.Then ethyl acetate and acetone is added successively wherein, for purifying so that can with the tetrazolium mesylate of safety and efficient manner production (I).
In above process, preferably with the amount application methylsulfonic acid of 1 to 1.5 equivalent of the compound of the formula (IV) based on 1 equivalent, described methylsulfonic acid is as the combined acid of the compound of formula (IV).
Further, ethyl acetate and acetone may be used for purifying.Preferably the formula (IV) based on 1g compound within the volume range of 1 to 5mL, apply ethyl acetate.Acetone can be applied in aqueous, preferably the aqueous acetone solution of 95%, the formula (IV) based on 1g compound within the volume range of 15 to 25mL.
As mentioned above, use the compound of formula (II) only can apply methyl alcohol and acetone for the preparation of the method for the present invention of tetrazolium mesylate, and do not use column chromatography, obtain the compound with highly purified formula (IV) with high yield.Therefore; use condensation reagent (such as 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N with comprising; N-bicyclic ethyl carbodiimide, N; N-DIC and 1-cyclohexyl-3-(2-morpholinyl ethyl) carbodiimide methyl tosylate) the traditional method of acidylate compare; method of the present invention can prepare high-purity product by simply filtering; therefore, which provide and be suitable for calculating very much and method easily of scale operation.
Simultaneously; as shown in following reaction scheme 4; by under the existence of triphenylphosphine and alkali, adopt the reaction of the compound of the compound of formula (VI) and formula (V) that the compound of the formula (II) of application in above-mentioned acidylate (step 1) can be prepared in.
reaction scheme 4
Particularly, at alkali and triphenylphosphine (PPH
3) existence under, by adopting 2 of formula (VI), the chromene acid of the two benzothiazole of 2'-bis-sulphur and formula (V) in organic solvent, reaction within the temperature range of 20 to 25 DEG C 1 to 3 hour, can the 4-oxo-4H-chromene-2-carbothionic acid S-benzothiazole-2-base ester of (II) for the preparation, wherein said organic solvent is selected from methylene dichloride (CH
2cl
2), diethyl ether, ethyl ester, tetrahydrofuran (THF) and composition thereof, preferred methylene dichloride, and described alkali is selected from triethylamine (NEt
3), pyridine, imidazoles, diisopropylethylamine (DIPEA), DMAP (DMAP) and composition thereof, preferred triethylamine.If the reaction times, more than 3 hours, may form the impurity as by product.
In the reaction, preferably with the compound of the amount applying equation (VI) of 1 to 2 equivalent of the compound of the formula (V) based on 1 equivalent.
Equally, preferably described triphenylphosphine is applied with the amount of 1 to 2 equivalent of the compound of the formula (V) based on 1 equivalent.
Preferably apply described alkali with the amount of 1 to 2 equivalent of the chromene acid of the formula (V) based on 1 equivalent.
Further, as shown in reaction scheme 5, for the preparation of in the method for the present invention of tetrazolium mesylate, compound as the formula (III) of starting raw material can be prepared by following method, it comprises: (step 1) adopts the compound of the compound of formula (VII) of formula (VIII) through cyclization, to obtain the compound of formula (IX); (step 2) compound of formula (IX) by using metal and acid reduction and obtaining in step before.
reaction scheme 5
Wherein Me represents methyl group.
First, the compound experience cyclisation of formula (VII) and formula (VIII) is to obtain the nitrophenyl tetrazole compound of formula (IX).
Particularly, under the existence of Sodium Nitrite and hydrochloric acid, compound reaction in aqueous solution (ethanolic soln of such as 50%) of permissive type (VII), to obtain diazonium salt.The compound and the pyrido that add formula (VIII) wherein stir, and maintain temperature of reaction in 10 DEG C or lower simultaneously.Reaction mixture be heated to room temperature and stir further, adopting 2.5N hydrochloric acid soln, sodium bicarbonate and water wash, then adopt dichloromethane extraction.After removing organic layer, add methyl alcohol for crystallization, to obtain compound as the formula (IX) of end product [see people such as SuketakaIto, Bulletin of the Chemical Society of Japan, Vol49 (7), 1920-1923 (1976)].
At this, as shown in following reaction scheme 6, reacted by the compound of the compound and formula (X) that adopt formula (XI) with the compound obtaining formula (XII), then the compound of metal and sour reduction-type (XII) is used, can the compound of (VII) for the preparation.
reaction scheme 6
Wherein Me represents methyl group.
Particularly, at Carbon Dioxide calcium (K
2cO
3) and sodium iodide (NaI) existence under, the compound of employing formula (XI) is at solvent (such as N, N-dimethylformaldehyde) in, along with stirring, make the compound of formula (X) within the temperature range of 70 to 100 DEG C through reaction, to obtain the nitrophenyl isoquinoline compound of formula (XII).Then, in the aqueous solution (ethanolic soln of such as 50%), metal and acid is used to make the compound of dry formula (XII) through reaction, to obtain the aminophenyl isoquinoline compound of formula (VII), wherein said metal chosen from Fe, tin, zinc and nickel, preferred iron, and described acid is selected from hydrochloric acid, nitric acid, sulfuric acid, acetic acid and composition thereof.
Reduction can carry out 3 hours in 80 DEG C.After the reduction, the sodium chloride aqueous solution of 10% can be added wherein for neutralization, and be filtered by Celite bed course.After removing organic layer, ether is adopted residue to be solidified, to obtain the compound of formula (VII).In reduction, described metal can be applied with the amount of 2 to 10 equivalents of the compound of the formula (XII) based on 1 equivalent, and described acid can be applied with the amount of 0.1 to 0.5 equivalent of the compound of the formula (XII) based on 1 equivalent.
Further, as shown in reaction scheme 7, by the compound reaction of the compound and formula (XIII) that adopt formula (XIV), can the compound of (VIII) for the preparation.
reaction scheme 7
Wherein Me represents methyl group.
Particularly, in ethanol, the compound of the compound of formula (XIII) of employing formula (XIV) within the temperature range of 70 to 80 DEG C through reaction, then by filtering and drying process, to obtain the compound of formula (VIII) [see people such as Suketaka Ito, Bulletin of theChemical Society of Japan, Vol49 (7), 1920-1923 (1976)].
In reaction scheme 5, metal and acid is used to make the compound of the formula (IX) obtained in step 1 subsequently through reduction, the compound (step 2) of (III) for the preparation.
Particularly, the metal in acid is used to make the compound of formula (IX) through reduction, to obtain the compound of formula (III), wherein said metal chosen from Fe, tin, zinc and nickel, preferred iron, and described acid is selected from hydrochloric acid, nitric acid, sulfuric acid, acetic acid and composition thereof, preferred acetic acid, the aqueous acetic acid of such as 50%.
Reduction is preferable over 80 DEG C and carries out 3 hours.After the reduction, the mixture of gained is filtered by Celite bed course, then neutralizes.After removing organic layer, residue is stirred in methyl alcohol the compound of the formula that obtains (III).
In described reduction, described metal can be applied with the amount of 5 to 15 equivalents of the compound of the formula (IX) based on 1 equivalent, and described acid can be applied at the compound of the formula (IX) based on 1g within the volume range of 2 to 5mL.
As mentioned above, in the production process of the compound of formula (III) and formula (VII), the present invention is applied metal and acid in reduction process, replace the palladium that uses in traditional method and gaseous hydrogen, so that it can reduce the reaction times, and reduce the risk of blast due to the security that improve reduction.
According to another aspect of the present invention, which provide the compound of formula (II), the compound of described formula (II) is for the preparation of the tetrazolium mesylate of formula (I).
Further, which provide the method for the compound for the preparation of formula (II), described method comprises in the presence of base, adopts the step of the compound of formula (VI) and the compound reaction of formula (V).
Hereinafter, more specifically describe the present invention by the following example, but be to provide these embodiments only for purposes of illustration, and the present invention is not restricted to wherein.
Embodiment: N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji) ethyl) phenyl)-2H-tetrazolium-5-base)-4,5-Dimethoxyphenyls) preparation of-4-oxo-4H-chromene-2-carboxamide mesylate salt
1-1) 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline
By the DMF of 5L, 2-(4-nitrophenyl) ethyl bromide (1.0kg, 4.35mol) and 6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (DTIH; 1.0kg, 4.35mol) join in reactor, and stir.Add salt of wormwood (1.80kg, 13mol) and sodium iodide (780g, 5.20mol) wherein, reactor is heated to 100 DEG C, and stir 12 hours further.After being completed by tlc (eluent: chloroform/methanol=15/1) detection reaction, reaction mixture is cooled to room temperature.
The cold water of 20L is joined in independent reactor, the reaction mixture obtained in step before being then slowly added in wherein, then stir 4 hours.The mixture of gained is filtered, adopts the water cleaning of 3L, then adopt warm air in 40 DEG C of dryings in an oven, to obtain title compound (1.34kg, 90%).
1H-NMR(CDCl
3)d:8.17(d,2H),7.43(d,2H),6.62(s,1H),6.54(s,1H),3.87(s,3H),3.85(s,3H),3.66(s,2H),3.03(t,2H),2.82-2.78(m,6H)。
1-2) 4-(2-(6,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji)-ethyl)-aniline
50% aqueous ethanolic solution of iron (1.27kg, 23.48mol), hydrochloric acid (127mL, 1.54mol) and 6.7L is joined in reactor, and stirs 1 hour in 80 DEG C.Slowly be added in 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3, the 4-tetrahydroisoquinoline (1.3kg, 3.91mol) that obtains in step 1-1 wherein totally one hour, then stir 3 hours in 80 DEG C.After checking that reaction completes by tlc (eluent: chloroform/methanol=15/1), reaction mixture is cooled to room temperature.Add the methylene dichloride of 5.3L and the water of 5.3L wherein, by 10% aqueous sodium hydroxide solution adding 804mL, reaction mixture is neutralized.The reaction mixture of gained is filtered by Celite bed course and adopts the methylene dichloride of 3L to clean.Organic layer is collected, via dried over mgso, then filters.Solvent under reduced pressure is removed, and adopts warm air in 40 DEG C of dryings in an oven, to obtain title compound (1.05 kg, 90%).
1H-NMR(CDCl
3)d:7.02(d,2H),6.65-6.53(m,4H),3.84(s,3H),3.83(s,3H),3.63(s,2H),3.57(s,2H),2.84-2.86(m,8H)。
2) 4,5-dimethoxy-2-nitro Tosylhydrazones
The ethanol of 12.5L, p-toluene sulfonyl hydrazide (1kg, 5.37mol) and 6-nitro veratryl aldehyde (1.2kg, 5.907mol) are joined in reactor, is then heated to 80 DEG C, then stir 6 hours.After checking that reaction completes by tlc (eluent: chloroform/methanol=15/1), reaction mixture is cooled to room temperature.The mixture of gained is filtered, adopts the ethanol purge of 12.5L, then adopt warm air in 40 DEG C of dryings in an oven, to obtain title compound (1.47kg, 99.6%).
1H-NMR(CDCl
3)d:8.48(s,1H),8.08(s,1H),7.89(d,2H),7.59(s,1H),7.42(s,1H),7.33(d,2H),4.02(s,3H),3.98(s,3H),2.44(s,3H)。
3) 4-oxo-4H-chromene-2-carbothionic acid S-benzothiazole-2-base ester
The methylene dichloride of chromene-2-formic acid (700g, 3.68mol), 2,2'-bis-sulphur two benzothiazine (1.47kg, 4.42mol), triphenylphosphine (1.16kg, 4.42mol) and 14.7L is joined in reactor, and stirs.Triethylamine (616mL, 4.42mol) in 2L methylene dichloride is slowly joined in reaction mixture, and stirs 6 hours.After the reaction was completed, the mixture of gained is filtered, adopt the acetone cleaning of 4L, then adopt warm air in 40 DEG C of dryings in an oven, to obtain title compound (0.99kg, 80%).
1H-NMR(CDCl
3)d:8.30(d,1H),8.16(d,1H),8.01(d,1H),7.88(t,1H),7.70(d,1H),7.61-7.31(m,3H),7.15(s,1H)。
4) 2-(4-(5-(4,5-dimethoxy-2-nitrophenyl)-2H-tetrazolium-2-base) styroyl)-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline
By the 4-(2-(6 obtained in step 1-2,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji)-ethyl)-aniline (1.0kg, 3.2mol), 50% aqueous ethanolic solution of 3L and hydrochloric acid (850mL, 12.5mol) join in reactor A, and in 0 DEG C of stirring.Sodium Nitrite (227g, 3.3mol) in 330ml water is slowly joined in reaction mixture, and stirs 3 hours.
The pyridine of 4,5-dimethoxy-2-nitro Tosylhydrazone (1.2kg, 3.2mol) and 12L obtained in step 2 is joined in the reactor B of 20L, and is cooled to 0 DEG C.Add the mixture coming from reactor A wherein lentamente, then in stirring at room temperature 6 hours.After checking that reaction completes by tlc (eluent: chloroform/methanol=15/1), adopt the methylene dichloride of 12L and the water extractive reaction mixture of 12L.Organic layer is collected, adopts the 2.5N hydrochloric acid cleaning three times of 18L and adopt sodium hydrogen carbonate solution to clean.Organic layer is dry, and underpressure distillation.By the methanol mixed of residue and 10L, and stir 4 hours.The mixture of gained is filtered and adopts warm air in 40 DEG C of dryings in an oven, to obtain title compound (1.08kg, 62%).
1H-NMR(CDCl
3)d:8.08(d,2H),7.66(s,1H),7.45(d,2H),7.32(s,1H),6.59(d,2H),4.03(s,6H),3.85(s,6H),3.68(s,2H),3.01(m,2H),2.84(m,6H)。
5) 2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji) ethyl) benzene
base)-2H-tetrazolium-5-base)-4,5-dimethoxyanilines
50% aqueous acetic acid of iron (433g, 7.76mol) and 5.4L is joined in reactor, and stirs 1 hour in 80 DEG C.Add the 2-(4-(5-(4 obtained in step 4 wherein lentamente, 5-dimethoxy-2-nitrophenyl)-2H-tetrazolium-2-base) styroyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.06kg, 1.94mol) totally 2 hours, then stirs 1 hour.After checking that reaction completes by tlc (eluent: chloroform/methanol=15/1), by reactor cooling to room temperature.Add the chloroform of 5.3L and the water of 2.4L wherein, and the mixture of gained is filtered by Celite bed course.Organic layer is collected, along with stirring, adds the saturated sodium bicarbonate solution of 6.6L wherein lentamente.Organic layer is collected, uses the chloroform of 1.25L to be extracted further by water layer.By the organic layer of gained via dried over mgso, then underpressure distillation is to remove solvent.By the methanol mixed of residue and 10.6L, then stir.The mixture of gained is filtered, and adopts warm air in 40 DEG C of dryings in an oven, to obtain title compound (0.87kg, 87%).
1H-NMR(CDCl
3)d:8.14(d,2H),7.75(s,1H),7.49(d,2H),6.63(d,2H),6.40(s,1H),5.34(d,2H),3.97(d,6H),3.89(s,6H),3.72(s,2H),3.06(t,2H),2.91-2.84(m,6H)。
6) N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji) ethyl) benzene
base)-2H-tetrazolium-5-base)-4,5-Dimethoxyphenyls)-4-oxo-4H-chromene-2-methane amide
By the 2-(2-(4-(2-(6 obtained in steps of 5,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji) ethyl) phenyl)-2H-tetrazolium-5-base)-4,5-dimethoxyaniline (850g, 1.6mol), the 4-oxo-4H-chromene-2-carbothionic acid S-benzothiazole-2-base ester (723g obtained in step 3,2.1mol) and the methylene dichloride of 17L join in reactor, and in stirring at room temperature 6 hours.After reaction completes by tlc (eluent: chloroform/methanol=15/1) inspection, add the methyl alcohol of 1.1L and 95% aqueous acetone solution of 35.7L wherein successively, then in stirring at room temperature 16 hours.The mixture of gained is filtered, adopts the acetone cleaning of 4.3L, adopt warm air in 40 DEG C of dryings in an oven, to obtain title compound (1.10kg, 97%).
1H-NMR(CDCl
3)d:12.53(s,1H),8.60(s,1H),8.23(d,1H),8.14(d,2H),7.77(d,2H),7.74(s,1H),7.50-7.44(m,3H),7.26(d,2H),6.60(d,2H),4.01(s,6H),3.87(s,6H),3.70(s,2H),3.08(t,2H),3.02-2.83(m,6H)。
7) N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji) ethyl) benzene
base)-2H-tetrazolium-5-base)-4,5-Dimethoxyphenyls)-4-oxo-4H-chromene-2-amide mesylate
By the N-(2-(2-(4-(2-(6 obtained in step 6,7-dimethoxy-3,4-dihydro-isoquinoline-2 (1H)-Ji) ethyl) phenyl)-2H-tetrazolium-5-base)-4,5-Dimethoxyphenyl)-4-oxo-4H-chromene-2-methane amide (1.06kg, 1.54mol) be dissolved in the mixing solutions of the chloroform of 18.1L and the methyl alcohol of 1.06L, and the mixture of gained is filtered.Add methylsulfonic acid (102mL, 1.57mol) in 300mL ethyl acetate wherein lentamente totally 30 minutes.Add the ethyl acetate totally 1 hour of 3.95L wherein lentamente, then in stirring at room temperature 16 hours.The mixture of gained is filtered, adopts the ethyl acetate cleaning of 1L, and adopt warm air in 40 DEG C of dryings in an oven.
Use chloroform to make product first time recrystallization, then filter, adopt ethyl acetate cleaning, and adopt warm air in 40 DEG C of dryings in an oven.Use mixed solvent (methylene chloride/methanol/ethyl acetate=17/1/4) by dry solid second time recrystallization to obtain crystalline solid.In order to remove residual solvent (i.e. methylene dichloride), the aqueous acetone solution of product and 95% being mixed, then stirs 16 hours.The mixture of gained is filtered, and adopts warm air in 40 DEG C of dryings in an oven, to obtain title compound (0.84kg, 70%).
Mass spectrum (ESI) calculated value C
38h
36n
6o
7;
M/z688.26 (M+H)+; Observed value, m/z689.32 (M+H)+
1H-NMR(CDCl
3)d:12.43(s,1H),11.66(s,1H),8.49(s,1H),8.17(d,1H),8.06(d,2H),7.79-7.67(m,2H),7.54(d,3H),7.46(t,1H),7.14(s,1H),6.67(d,2H),4.78(d,1H),4.19-4.12(m,1H),3.96-3.87(m,12H),3.56-3.36(m,6H),3.04(d,1H),2.78(s,3H)。
Comparative example
Tetrazolium methylsulfonic acid is prepared according to the process disclosed in WO2005/033097; it comprises the reduction using palladium and gaseous hydrogen, and uses the acidylate of 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and condensation reagent DMAP (DMAP).
Experimental example
The method of the present invention that metal and acid are carried out reducing and the traditional method using palladium and hydrogen is used in order to compare to comprise, the purity of product, the security of reduction process and economic feasibility in embodiment and comparative example are assessed, and result summed up in Table 1, wherein the result of comparative example can supply 2009-2010 Aldrich Catalog ref.
As shown in table 1, the two reduction process produce target product there is identical purity, but, compared with traditional method, according to reduction process of the present invention can with safer, prepare target product without explosion hazard and mode to one's profit.
< shows 1>
Equally, in order to compare the method for the present invention of the compound of use formula (II) and use the efficiency of 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and the traditional method as the DMAP (DMAP) of condensation reagent, the yield percentage of the compound of embodiment and comparative example Chinese style (IV), purity and purification process are summarised in following table 2.
As shown in table 2, compared with traditional method, method of the present invention can produce the compound of the formula (IV) with higher yield percentage and purity.Can show equally, method of the present invention can obtain pure chemical product by means of only recrystallization, without the need to extra column chromatography process.
< shows 2>
Embodiment | Comparative example | |
Compound used | The compound of formula (II) | EDCI/DMAP |
Productive rate | 95% | 65% |
Purity | >98% | 94% |
Purification process | Recrystallization | Column chromatography |
Although about above-mentioned specific embodiment, invention has been described, should be realized that, those skilled in the art can make various modification and change to the present invention, and it falls within the scope of the present invention that is defined by the claims equally.
Claims (22)
1., for the preparation of a method for the tetrazolium mesylate of formula (I), it comprises the following step:
The compound of the compound acylation formula (III) of employing formula (II), to obtain the compound of formula (IV); With
Methylsulfonic acid is joined in the compound of formula (IV):
2. method according to claim 1, wherein said acidylate is carried out in polar aprotic solvent, and described polar aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), ethyl ester, acetone, DMF, acetonitrile, methyl-sulphoxide and composition thereof.
3. method according to claim 1, wherein under the existence of triphenylphosphine and alkali, the compound by adopting the reaction of the compound of the compound of formula (VI) and formula (V) to prepare described formula (II):
4. method according to claim 3, wherein said alkali is selected from triethylamine, pyridine, imidazoles, diisopropylethylamine, DMAP and composition thereof.
5. method according to claim 3, the reaction of the compound of wherein said formula (V) and the compound of described formula (VI) is carried out in organic solvent, and described organic solvent is selected from methylene dichloride, ether, ethyl ester, tetrahydrofuran (THF) and composition thereof.
6. method according to claim 3, wherein along with stirring, the reaction of the compound of described formula (V) and the compound of described formula (VI) is being carried out 1 to 3 hour within the temperature range of 20 to 25 DEG C.
7. method according to claim 1, the method wherein by comprising the following step prepares the compound of described formula (III):
The compound of the compound of formula (VII) of employing formula (VIII) through cyclization, to obtain the compound of formula (IX); With
Use the compound of metal and sour reduction-type (IX):
8. method according to claim 7, wherein said metal chosen from Fe, tin, zinc and nickel.
9. method according to claim 7, wherein applies described metal with the amount of 5 to 15 equivalents of the compound of the described formula (IX) based on 1 equivalent.
10. method according to claim 7, wherein said acid is selected from hydrochloric acid, nitric acid, sulfuric acid, acetic acid and composition thereof.
11. methods according to claim 7, wherein the described formula (IX) based on 1g compound within the volume range of 2 to 5mL, apply described acid.
12. methods according to claim 7, wherein reacted by the compound of the compound and described formula (X) that adopt described formula (XI) with the compound obtaining formula (XII), the compound then by using the compound of metal and the acid described formula of reduction (XII) to prepare described formula (VII):
13. methods according to claim 12, wherein for reducing the described metal chosen from Fe of compound of described formula (XII), tin, zinc and nickel.
14. methods according to claim 12, wherein with the application of the amount of 2 to 10 equivalents of the compound of the described formula (XII) based on 1 equivalent for reducing the described metal of compound of described formula (XII).
15. methods according to claim 12, are wherein selected from hydrochloric acid, nitric acid, sulfuric acid, acetic acid and composition thereof for reducing the described acid of compound of described formula (XII).
16. methods according to claim 12, wherein with the application of the amount of 0.1 to 0.5 equivalent of the compound of the described formula (XII) based on 1 equivalent for reducing the described acid of compound of described formula (XII).
17. methods according to claim 7, the compound wherein by adopting the reaction of the compound of the compound of described formula (XIV) and described formula (XIII) to prepare described formula (VIII):
The compound of 18. formulas (II):
The method of the compound of 19. 1 kinds of preparation formulas (II), under it is included in the existence of triphenylphosphine and alkali, adopts the step of the compound of described formula (VI) and the compound reaction of described formula (V):
20. methods according to claim 19, wherein said alkali is selected from triethylamine, pyridine, imidazoles, diisopropylethylamine and DMAP.
21. methods according to claim 19, wherein said reaction is carried out in organic solvent, and described organic solvent is selected from methylene dichloride, ether, ethyl ester, tetrahydrofuran (THF) and composition thereof.
22. methods according to claim 19, wherein along with stirring, described reaction is being carried out 1 to 3 hour within the temperature range of 20 to 25 DEG C.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020100003835A KR101466245B1 (en) | 2010-01-15 | 2010-01-15 | Method for preparing methanesulfonic acid salt and novel compound used therein |
KR10-2010-0003835 | 2010-01-15 | ||
PCT/KR2011/000291 WO2011087316A2 (en) | 2010-01-15 | 2011-01-14 | Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102812020A CN102812020A (en) | 2012-12-05 |
CN102812020B true CN102812020B (en) | 2015-03-18 |
Family
ID=44304835
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201180005610.5A Active CN102812020B (en) | 2010-01-15 | 2011-01-14 | Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same |
Country Status (20)
Country | Link |
---|---|
US (2) | US8680277B2 (en) |
EP (1) | EP2524916B1 (en) |
JP (1) | JP5575921B2 (en) |
KR (1) | KR101466245B1 (en) |
CN (1) | CN102812020B (en) |
AU (1) | AU2011205891B2 (en) |
BR (1) | BR112012017448B1 (en) |
CA (1) | CA2786434C (en) |
DK (1) | DK2524916T3 (en) |
ES (1) | ES2514340T3 (en) |
HK (1) | HK1177211A1 (en) |
IL (1) | IL220851A (en) |
MX (1) | MX2012007868A (en) |
NO (1) | NO342589B1 (en) |
NZ (1) | NZ601805A (en) |
PL (1) | PL2524916T3 (en) |
RU (1) | RU2509769C1 (en) |
SG (1) | SG182430A1 (en) |
WO (1) | WO2011087316A2 (en) |
ZA (1) | ZA201206084B (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101986683B1 (en) * | 2012-12-13 | 2019-06-10 | 한미약품 주식회사 | Solid dispersion with improved solubility comprising tetrazole derivative as an active ingredient |
CN103804352B (en) * | 2014-01-23 | 2017-06-13 | 中国药科大学 | Triazole phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application |
JO3737B1 (en) * | 2015-07-21 | 2021-01-31 | Athenex Therapeutics Ltd | THERAPEUTIC COMBINATIONS OF ORALLY ADMINISTERED PACLITAXEL AND A P-gp INHIBITOR FOR THE TREATMENT OF CANCER |
US11165722B2 (en) | 2016-06-29 | 2021-11-02 | International Business Machines Corporation | Cognitive messaging with dynamically changing inputs |
US20220135548A1 (en) | 2019-02-14 | 2022-05-05 | Teva Pharmaceuticals International Gmbh | Solid state forms of n-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl)ethyl]phenyl}-2h-tetrazol-5-yl)-4,5- dimethoxyphenyl]-4-oxo-4h-chromene-2-carboxamide and of its mesylate salt |
WO2020194175A1 (en) * | 2019-03-25 | 2020-10-01 | Dr. Reddy's Laboratories Limited | Solid forms of encequidar mesylate and processes thereof |
WO2020230037A1 (en) * | 2019-05-13 | 2020-11-19 | Dr. Reddy's Laboratories Limited | Alternate process for the preparation of encequidar |
WO2021044350A1 (en) * | 2019-09-04 | 2021-03-11 | Dr. Reddy’S Laboratories Limited | Solid forms of encequidar mesylate and processes thereof |
US20230278990A1 (en) | 2020-07-10 | 2023-09-07 | Teva Czech Industries S.R.O | Solid state forms of n-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl)ethyl]phenyl}-2h-tetrazol-5-yl)-4,5-dimethoxyphenyl]-4-oxo-4h-chromene-2-carboxamide mesylate salt |
CN116964044A (en) | 2020-10-07 | 2023-10-27 | 希华医药有限公司 | Acetamido-phenyltetrazole derivatives and methods of use thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005033097A1 (en) * | 2003-10-07 | 2005-04-14 | Hanmi Pharm. Co., Ltd. | P-glycoprotein inhibitor, method for preparing the same and pharmaceutical composition comprising the same |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL129871A (en) * | 1994-05-06 | 2003-11-23 | Pharmacia & Upjohn Inc | Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections |
KR100508019B1 (en) * | 2003-07-19 | 2005-08-17 | 한미약품 주식회사 | Method for the preparation of highly pure 1-androstene derivatives |
US7279471B2 (en) * | 2004-04-15 | 2007-10-09 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
KR100686695B1 (en) * | 2005-06-11 | 2007-02-26 | 주식회사 에스텍파마 | A process for preparing pranlukast or its hydrate and a synthetic intermediate thereof |
US20070161791A1 (en) * | 2006-01-09 | 2007-07-12 | Narsimha Reddy Penthala | Process for the preparation of terazosin hydrocloride dihydrate |
-
2010
- 2010-01-15 KR KR1020100003835A patent/KR101466245B1/en active IP Right Grant
-
2011
- 2011-01-14 EP EP11733103.3A patent/EP2524916B1/en active Active
- 2011-01-14 SG SG2012050472A patent/SG182430A1/en unknown
- 2011-01-14 CN CN201180005610.5A patent/CN102812020B/en active Active
- 2011-01-14 PL PL11733103T patent/PL2524916T3/en unknown
- 2011-01-14 MX MX2012007868A patent/MX2012007868A/en active IP Right Grant
- 2011-01-14 AU AU2011205891A patent/AU2011205891B2/en active Active
- 2011-01-14 NZ NZ601805A patent/NZ601805A/en unknown
- 2011-01-14 US US13/522,272 patent/US8680277B2/en active Active
- 2011-01-14 RU RU2012134783/04A patent/RU2509769C1/en active
- 2011-01-14 CA CA2786434A patent/CA2786434C/en active Active
- 2011-01-14 WO PCT/KR2011/000291 patent/WO2011087316A2/en active Application Filing
- 2011-01-14 DK DK11733103.3T patent/DK2524916T3/en active
- 2011-01-14 JP JP2012548895A patent/JP5575921B2/en active Active
- 2011-01-14 BR BR112012017448-7A patent/BR112012017448B1/en active IP Right Grant
- 2011-01-14 ES ES11733103.3T patent/ES2514340T3/en active Active
-
2012
- 2012-07-10 IL IL220851A patent/IL220851A/en active IP Right Grant
- 2012-07-20 NO NO20120841A patent/NO342589B1/en unknown
- 2012-08-14 ZA ZA2012/06084A patent/ZA201206084B/en unknown
-
2013
- 2013-04-18 HK HK13104698.2A patent/HK1177211A1/en unknown
-
2014
- 2014-02-03 US US14/171,318 patent/US8940908B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005033097A1 (en) * | 2003-10-07 | 2005-04-14 | Hanmi Pharm. Co., Ltd. | P-glycoprotein inhibitor, method for preparing the same and pharmaceutical composition comprising the same |
Non-Patent Citations (1)
Title |
---|
《2"-Benzothiazolythioesters of N-Substituted Alpha Amino Acids: Versatile Intermediates for Synthesis of ACE Inhibitors》;Girij Pal Singh;《Synthetic Communications》;20070728;第35卷(第2期);243-248 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102812020B (en) | Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same | |
JP6061158B2 (en) | Synthesis intermediate of 6- (7-((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -N-methyl-1-naphthamide, or a pharmaceutically acceptable salt thereof, and its use | |
KR20120125630A (en) | Processes of synthesizing dihydropyridophthalazinone derivatives | |
CN105330540A (en) | Preparation method for montelukast sodium intermediate | |
CN102603627B (en) | Naphthlamide derivative used as protein kinase inhibitor and histone deacetylase inhibitor and preparation method of naphthlamide derivative | |
JP2013537875A5 (en) | ||
CN101654416B (en) | N-[3-nitro-4-methyl-phenyl]-4-aldehyde group-benzamide and preparation method thereof as well as preparation method of derivatives thereof | |
CN103864773A (en) | Preparation method for rivaroxaban and intermediate thereof | |
CN103739541B (en) | The preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridones | |
CN105111163A (en) | Synthesis method of 4-(4-aminophenyl)-3-morpholone | |
CN107892669B (en) | A method of by borrowing hydrogen to react synthesis of quinoline derivatives | |
CN106146385A (en) | A kind of synthetic method of triglyceride transfer protein enzyme inhibitor | |
CZ20697A3 (en) | Process of stereoselective preparation of heterobicyclic alcohol enantiomer | |
CN115108926B (en) | Intermediate compound for preparing erdasatinib and preparation method | |
CN104098556A (en) | Novel synthetic process for rivaroxaban | |
CN102131761A (en) | Method for producing alpha-hydroxyester compound | |
CN102190650A (en) | Method for preparing indoquinoline tartrate | |
CN102171175A (en) | Method for producing tetrafluoro compound | |
EP1698611A1 (en) | Process for producing phenylacetic acid derivative | |
CN102838609B (en) | Azabicyclo [3.3.0] octane derivative, as well as preparation method and application thereof | |
CN103936665B (en) | A kind of synthetic method of 4-substituted piperidine derivative | |
CN107501236A (en) | A kind of preparation method of 2 substituted benzimidazole derivatives | |
CN107778193A (en) | A kind of preparation method of 2 aminomethyl phenyl azido compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1177211 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1177211 Country of ref document: HK |